Drug delivery technology has been used extensively for the purpose of delivering agents to desired targets for many years. A variety of methods and routes of administration have been developed to deliver pharmaceuticals, such as small molecular drugs and other biologically active compounds (e.g., peptides, hormones, proteins, and enzymes). Examples of various drug delivery methods are disclosed, for example, in WO 2012/037358, WO 2009/132265, WO 2005/082023, WO 2012/113847, WO 2012/131527, Chiu et al., “Synthesis, Hydrolytic Reactivity, and Anticancer Evaluation of N- and O- Trioganosilyated Compounds as New Types of Potential Prodrugs,” J. Pharm. Sci., 71(5):542-551 (1982), Millership et al., “Prodrugs Utilizing Organosilyl Derivation: An Investigation of the Long-term Androgenic and Myotrophic Activities of Silyl Derivatives of Testosterone,” J. Pharm. Sci., 77(2):116-119 (1988), Parrott et al., “Tunable Bifunctional Silyl Ether Cross-Linkers for the Design of Acid-Sensitive Biomaterials,” J. Am. Chem. Soc, 132:17928-17932 (2010), and Leamon et al., “Delivery of Macromolecules into Living Cells: A Method That Exploits Folate Receptor Endocytosis” Proc. Natl. Acad. Sci. U.S.A. 88(13):5572-5576 (1991). Drug delivery technologies include liposomes and nano or microparticles.
Recently, antibody-drug conjugates (ADCs) have been devised to enhance the efficacy of antibody therapy. ADCs consist of a targeting antibody, a cytotoxic drug (warhead or therapeutic agent), and a linker system that attaches the two. With this delivery method, release of the free drug is normally necessary for the drug to elicit its desired action. Common techniques of releasing the cytotoxic drug include hydrazone hydrolysis, enzymatic cleavage of peptides (e.g. p-aminobenzyl alcohol release technology, WO 2005/082023), and reduction of disulfides. Certain other functional moieties have been used such as esters, but esters often can be too labile to achieve the long plasma half-lives desired for the intact conjugate.
Silyl ethers are a group of compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si—O—R4 where R4 is an alkyl group or an aryl group. Silyl ethers are commonly used as protecting groups of an alcohol functional group during organic synthesis (Wuts et al., “Greene's Protective Groups in Organic Synthesis,” 4th edition. John Wiley & Sons, Inc. Hoboken, N.J. (2007)). R1R2R3 substituents can be widely varied providing access to a large array of silyl ethers that can possess differential properties. This feature makes silyl ethers attractive for application in selective protection and deprotection schemes in synthetic organic chemistry. The steric bulk and electronic properties of the substituents as well as the capacity of silicon to allow hypervalent species allow for a wide range of selective chemistry during formation and deprotection of silyl ether groups. Silyl ethers can be hydrolytically cleaved thereby providing a means to release free drug in an in vivo environment. Acid labile triggers such as hydrazones are known in the ADC field (Flygare et al. “Antibody-Drug Conjugates for the Treatment of Cancer,” Chem Biol Drug Des., 81:113-121 (2013)). The increased acidic environment of the endosomes (pH 5.5-6.2) and lysosomes (pH 4.5-5.0) relative to systemic circulation (pH 7.4-7.5) are thought to release the active drug. Silyl ether hydrolysis rates can be varied by changing the R1R2R3 substituents.
Accordingly, there is a need in the art for compounds and methods useful to facilitate delivery and release of desired compounds to a site of interest.
The present invention is directed to overcoming these and other deficiencies in the art.